Successful vaccination against category A-->C pathogens hinges on robust cell-mediated adaptive immune responses elicited by the vaccine adjuvant. Since none of the adjuvants currently approved for use in humans have been shown to elicit cell-mediated adaptive immune responses, the objective of this application is to develop an effective adjuvant for category A-->C pathogens. Published studies indicate that triggering the innate immune system is essential for generating effective cell-mediated adaptive immune responses. In preliminary studies in this laboratory, one particular chemokine encoded by a virus has been found to exhibit strong inflammatory properties in vivo, and subsequently to elicit strong antibody responses to co-injected antigen. In Specific Aim #1, this chemokine will be analyzed for its effects on human and mouse innate immune system cells; each cell type will be purified, treated with the chemokine and analyzed in functional assays. In Specific Aim #2, the human and mouse receptors for the chemokine will be cloned, characterized and used in high-throughput screens to identify agonists. In Specific Aim #3, the agonists will be optimized by medicinal chemistry and SAR studies, then given to Project 4 for analysis of adjuvanticity in animal vaccination models. In Specific Aim #4, the optimized lead agonist will be entered into clinical trials. The proposed studies on this promising novel chemokine and its receptor should lead to the development of an ideal adjuvant for vaccination against category A->C pathogens.